Blood, 15 December 2001, Vol. 98, No. 13, pp. 3857-3859
BRIEF REPORT
Autologous stem cell transplantation for HIV-associated
lymphoma
Amrita Krishnan,
Arturo Molina,
John Zaia,
Auayporn Nademanee,
Neil Kogut,
Joseph Rosenthal,
Doni Woo, and
Stephen J. Forman
From the Division of Hematology and Bone Marrow
Transplantation, Division of Pediatrics (Virology and Infectious
Disease, Bone Marrow Transplantation); City of Hope Medical Center,
Duarte, California; The City of Hope-Southern California Kaiser
Permanente Bone Marrow Transplant Program.
 |
Abstract |
Is peripheral stem cell mobilization followed by autologous stem
cell transplantation (ASCT) feasible in patients with human immunodeficiency virus (HIV)- associated lymphoma (HIV-L)?
Studies have demonstrated that, in the HIV- negative
(HIV
) setting, ASCT may improve lymphoma-free survival in
high-risk non-Hodgkin lymphoma (NHL) or relapsed Hodgkin
disease (HD) and NHL. Given the poor prognosis of HIV-L with
conventional chemotherapy, this dose-intensive approach was explored.
Nine patients with HIV-HD or NHL mobilized a median of
10.6 × 106 CD34+ cells/kg and engrafted
after ASCT. CD4 counts recovered to pretransplantation levels and HIV
viral loads were controlled in patients compliant with antiretroviral
therapy. Seven of 9 patients remain in remission from their lymphoma at
a median of 19 months after transplantation. Thus, patients with HIV-L
on antiretroviral therapy can engraft following ASCT. Prolonged
lymphoma remissions, without significant compromise of immune function,
can be seen, suggesting that ASCT can be used in selected patients with
HIV-L.
(Blood. 2001;98:3857-3859)
© 2001 by The American Society of Hematology.
| |
Introduction |
Highly active antiretroviral therapy (HAART)
has changed the natural history of human immunodeficiency virus (HIV)
infection by improving immune function in HIV-infected
individuals.18 However, multiple studies have shown no
impact of HAART on the incidence of acquired immunodeficiency syndrome
(AIDS)-related non-Hodgkin lymphoma (NHL) or Hodgkin disease
(HD).1-6
Earlier therapeutic approaches to HIV-associated lymphoma (HIV-L)
focused on reduction of chemotherapy dose intensity due to fears of
further worsening the immune function in these patients.7 In the era of HAART, more aggressive approaches are being
explored.8-11 In HIV-negative (HIV) patients
with relapsed aggressive NHL and HD, high-dose chemotherapy with
autologous stem cell transplantation (ASCT) is the optimal therapy.12 This modality has also been explored
in patients with NHL in first remission who are considered to be
at increased risk for relapse with conventional-dose
chemotherapy.13,14 We report here on our initial
experience using ASCT in patients with HIV-L receiving HAART.
| |
Study design |
Between March 1998 and May 2000, 9 HIV-L patients on HAART
received myeloablative chemotherapy followed by ASCT at our
institution. Informed consent was obtained from all patients in
accordance with the City of Hope Medical Center institutional review
board guidelines. The median age was 41.6 years (range, 11.4-54.3 years). Seven patients had NHL and 2 had HD (Table
1). The NHL patients who were in first
remission had high-risk features as defined by the international
prognostic index (IPI).15,19
All patients were on HAART (Table 1) at the time of stem cell
collection before transplantation and had undetectable HIV viral loads
(VLs). Stem cells were mobilized with a combination of chemotherapy and
10 µg/kg granulocyte colony-stimulating factor (G-CSF) and collected
as previously described.10 A median of 10.6 × 106 CD34+ cells/kg was collected.
Five patients had additional stem cells collected as part of a gene
therapy trial, which was reported separately.16
High-dose chemotherapy with the CBV regimen (cyclophosphamide 100 mg/kg
ideal body weight, 1,3-bis-(2-chloroethyl)1-nitrosourea (BCNU) 450 mg/m2, etoposide 60 mg/kg adjusted ideal body weight) was
administered to all patients.13,17 Autologous stem cells
were reinfused on transplantation day 0. Five patients, who were also
on the gene therapy trial, had genetically modified stem cells
(0.5-2.0 × 106 CD34+ cells/kg) reinfused
after the infusion of unmanipulated stem cells.16
Twenty-four hours after stem cell infusion, G-CSF (5 µg/kg) was
started and continued until engraftment. Routine anti-infective prophylaxis was administered to all patients as previously
described.10 Most patients were able to continue HAART
through the transplantation. Three patients missed one dose, one
missed 3 doses, and only one patient missed all doses due to
persistent nausea.
| |
Results and discussion |
Engraftment occurred in all 9 patients. White cell engraftment,
defined as an absolute neutrophil count greater than 500/µL, occurred
at a median of 11 days (range, 9-12). Platelet engraftment, defined as
platelet transfusion independence and a platelet count greater than
20 × 109/µL, occurred at a median of 10 days
(range, 7-15).
Infectious complications during the period of neutropenia up to the day
of engraftment were seen in 6 patients. These included coagulase-negative Staphylococcus or
Streptococcus pneumoniae bacteremia in 4 patients. One patient developed a dental abscess. On transplantation
day +11 one patient developed culture-negative sepsis, manifest as
hypotension, gastrointestinal bleeding, and skin erythema. Infectious
complications after engraftment included Clostridium
difficile colitis in one patient at day +38. Two patients developed an interstitial pneumonia between day +40 and day +60. One of
these patients also developed a lobar pneumonia in year 2 after
transplantation as well as Staphylococcus aureus bacteremia and recurrent sinusitis. One patient developed a bacterial pneumonia, presumably after influenza, at +21 months for which he required temporary ventilatory support. All patients responded to antimicrobials.
Opportunistic infections were seen in 3 patients
an uncomplicated
disseminated varicella zoster infection at 2 months after transplantation in one patient, cytomegalovirus viremia and fever at 37 days in another patient, and Pneumocystis carinii
pneumonia (PCP) at 8 months and cytomegalovirus retinitis at 17 months
after transplantation in one patient who stopped both PCP prophylaxis and antiretrovirals. All patients responded to treatment.
Conditioning regimen-related complications included grade 2 mucositis
in 6 patients and grade 2 hyperbilirubinemia in one patient. One of
these patients also had BCNU pneumonitis, presenting as interstitial
infiltrates at day +55; this responded well to oral prednisone. All
toxicity was graded according to common toxicity grading criteria
version 2.0.
The CD4 counts gradually decreased after transplantation in all 9 patients and reached a nadir of 138/µL (range, 25-411) at a median of
2 months in 7 evaluable patients (Figure
1). Two nonevaluable patients
died at approximately 4 months after transplantation with relapsed
lymphoma. Six of these 7 evaluable patients recovered CD4 counts to
pretransplantation levels by a median of 14 months (range, 2-28). One
patient (UPN 209) had the highest CD4 counts before transplantation
(> 1000/µL), which may account for the failure to return to this
baseline.
Six patients had a rise in their HIV VL in the first month following
the transplantation, whereas 3 patients maintained an undetectable VL
(Figure 2). In 5 of the 7 patients
evaluable at 12 months, the VL was at undetectable levels
(b-DNA assay or RNA polymerase chain reaction Roche Amplicor assay).
One patient (UPN202), had a significant rise at 18 months and one
(UPN406) at 36 months due to noncompliance with HAART. Two patients
(UPN203, UPN407) had a persistently high VL after transplantation.
UPN203 required multiple changes in his regimen. He was compliant with
HAART, hence his high VL may reflect the inability of HAART to
eradicate the latent HIV reservoir. Patient UPN407 stopped all
antiretroviral therapy for a prolonged period after transplantation for
psychosocial reasons, which explains the continued high VL.
We report here on the largest single institution series of patients
with HIV-L on HAART treated with ASCT. All patients received the same
high-dose chemotherapy conditioning and achieved long-term engraftment
with stem cell rescue in a time course similar to HIV
patients. Pre-engraftment infectious complications were similar to the
HIV setting with bacterial infections
predominating.12 Conditioning regimen-related
complications were also similar to the HIV setting in
that there was no increase in mucositis or hepatotoxicity associated
with combining HAART and high-dose chemotherapy. After transplantation,
the several opportunistic infections that occurred responded well to
treatment. In the majority of patients we have seen recovery of immune
function as manifest by low VL and rising CD4 counts. This is similar
to changes in immune parameters in HIV-L patients treated with CHOP and
concomitant antiretroviral therapy.20 Future studies will
address the pharmacokinetic effects of myeloablative therapy in
combination with HAART and the reconstitution of immune function after
ASCT. The effects of this approach on lymphoma-free survival remain to
be seen. The surviving patients have been followed for a median of 19.0 months (range, 12-36 months). Two patients relapsed with disease in the
bone marrow at 40 days and 95 days, respectively, and died. All other
patients remain in remission.
The advent of effective antiviral therapy now allows us to
administer dose-intensive and potentially curative chemotherapy to
HIV-infected individuals with lymphoma. Infectious complications can be
managed through a combination of prophylaxis and close monitoring after
transplantation. Hence, HIV status should no longer by itself preclude
ASCT for treatment of lymphoma.
| |
Acknowledgments |
The authors thank Sarah Cole and Celina Acedo for biostatistical
support and Diana Garcia for secretarial support.
| |
Footnotes |
Submitted May 3, 2001; accepted August 3, 2001.
Supported in part by United States Public Health Service grants
CA30206, CA33572, and AI 38592 and grant M01 RR-43 from the General
Clinical Research Center branch of the National Center for
Research Resources, National Institutes of Health. A.K. is the
recipient of a Lymphoma Research Foundation of America Fellowship Award. A.M. is the recipient of an American Cancer Society Clinical Oncology Career Development Award.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Amrita Krishnan, Division of Hematology and Bone
Marrow Transplantation, City of Hope National Medical Center, 1500 E
Duarte Rd, Duarte, CA 91010; e-mail: akrishnan{at}coh.org.
| |
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Abstract
Introduction
